Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118, USA.
Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Sci Adv. 2022 Jul 15;8(28):eabo6566. doi: 10.1126/sciadv.abo6566. Epub 2022 Jul 13.
Genome-wide association studies (GWAS) have identified dozens of loci associated with chronic obstructive pulmonary disease (COPD) susceptibility; however, the function of associated genes in the cell type(s) affected in disease remains poorly understood, partly due to a lack of cell models that recapitulate human alveolar biology. Here, we apply CRISPR interference to interrogate the function of nine genes implicated in COPD by GWAS in induced pluripotent stem cell-derived type 2 alveolar epithelial cells (iAT2s). We find that multiple genes implicated by GWAS affect iAT2 function, including differentiation potential, maturation, and/or proliferation. Detailed characterization of the GWAS gene demonstrates that it regulates iAT2 cell-cell junctions, proliferation, mitochondrial function, and response to cigarette smoke-induced injury. Our approach thus elucidates the biological function, as well as disease-relevant consequences of dysfunction, of genes implicated in COPD by GWAS in type 2 alveolar epithelial cells.
全基因组关联研究（GWAS）已经确定了数十个与慢性阻塞性肺疾病（COPD）易感性相关的基因座；然而，与疾病相关的基因在受影响的细胞类型中的功能仍知之甚少，部分原因是缺乏能够重现人类肺泡生物学的细胞模型。在这里，我们应用 CRISPR 干扰技术来研究 GWAS 中涉及 COPD 的九个基因在诱导多能干细胞衍生的 2 型肺泡上皮细胞（iAT2）中的功能。我们发现，GWAS 所涉及的多个基因影响 iAT2 的功能，包括分化潜能、成熟和/或增殖。对 GWAS 基因的详细表征表明，它调节 iAT2 细胞-细胞连接、增殖、线粒体功能以及对香烟烟雾诱导损伤的反应。因此，我们的方法阐明了 GWAS 中涉及 COPD 的基因在 2 型肺泡上皮细胞中的生物学功能以及功能障碍相关的疾病后果。
